There are over 300 million clinical episodes of malaria each year worldwide with over 1 million deaths, primarily in children under 5. Over 41% of the world's population lives in areas where malaria is transmitted. The global economic toll of malaria is staggering. In addition to contributing significantly towards overall childhood mortalit in the poorest nations, the disease is estimated to cause approximately a 1.3% reduction in economic growth in countries that bear a heavy malaria burden. Unfortunately, most of the drugs that are currently being used for malaria treatment were developed more than 30 years ago and many are derivatives of older drugs. In the absence of a large-scale effort to develop novel drugs against malaria, most antimalarials have now become ineffective due to widespread drug resistance. Investment in the discovery of new therapeutics for the treatment of malaria has been sparse and the number of new treatments introduced to the market is correspondingly low. Given the global toll of malaria and the spread of drug resistance, it is important to identif new chemical entities that can be developed into therapeutics for the treatment of drug-resistant malaria. The proposed research project seeks to discover novel chemical entities from marine microbes targeting the malaria parasite is timely and will provide entry into novel therapeutic interventions for the disease. Our approach will be to tap into the chemical and biological diversity of the Harbor Branch Oceanographic Institute Marine Microbial Culture Collection (HBMMCC) as a source of novel bioactive natural products. We will assay a novel library of marine microbe derived extracts for their ability to inhibit the growth of the malaria parasite usig the SYBR Green I Fluorescent assay. Active extracts will be dereplicated using Liquid-chromatography- mass spectroscopy (LC-MS) and NMR methodologies and those with the greatest potential for novel chemistry will be further profiled for their activity against a panel f drug resistant Plasmodium falciparum strains to define potency, and the mammalian cell lines to help assess therapeutic index. Extracts with strong potency against the malaria parasite, low toxicity to mammalian cells and novel chemistry will be taken through bioassay- guided fractionation to identify the structure of bioactive components. The proposed research is significant because at the end of this project we expect to have a portfolio of antimalarial hits PUBLIC HEALTH RELEVANCE: Malaria is one of the major tropical diseases afflicting over 300 million and killing about 1 million individuals annually. Majority of the current treatments fo malaria are becoming ineffective because of emergence of drug resistance parasites. Therefore, it is urgent to develop new malaria therapeutics to mitigate this serious problem. The proposed research project seeks to discover novel chemical entities from marine microbes targeting the malaria parasite is timely and will provide entry into novel therapeutic intervention for the disease.